Methods and compositions for treating periodontal disease with an inhibitor of secretory phospholipase A2

ABSTRACT

The present invention relates to methods of treating periodontal disease in a mammal. The methods include administering to an animal an s effective amount of an inhibitor of sPLA 2 . The inhibitors may be advantageously delivered as a composition that includes various carriers. In certain aspects of the invention, inhibitors used in the method include substituted indole or substituted pyrrole sPLA 2  inhibitors. Also provided are compositions that include the sPLA 2  carriers for oral delivery of the inhibitors.

REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/097,682, filed on Aug. 24, 1998, which is herebyincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Periodontal disease is an oral inflammatory disease that begins wheninflammation of gingival tissues (gingivitis) progresses to aninflammation of the periodontal attachment tissues. This inflammationmay eventually lead to breakdown of the periodontal attachment,periodontal pocket formation and bone loss-periodontitis. The diseasemay progress to the extent of causing tooth loss due to destruction ofthe tooth supporting bone. A similar course of events can take place inthe tissues surrounding dental implants (peri-implantitis), and canresult in gradual loosening and eventual loss of the implant.

The rate of progression of periodontal disease is extremely variable. Itis believed to be modulated by a complex interaction between subgingivalbacterial, the host defense system (including immune and inflammatoryresponses), and other local tissue factors. Methods of treatment,however, have traditionally focused on the bacterial component of thedisease.

The conventional approach to the treatment of periodontal diseaseinvolves initially removing subgingival bacterial plaque and calculusdeposits with scaling and root planing procedures and following-up withimproved oral hygiene procedures. If this treatment does not haltprogression of the disease, surgical reduction of periodontal tissues isoften performed, with the intention of decreasing the depth of theperiodontal pocket, thus decreasing the area available for bacterialcolonization and aiding mechanical removal of the microorganisms.Concurrent treatment with an antibacterial agent may also be used tofurther reduce bacterial numbers.

Antibiotics such as tetracycline derivatives are commonly used. Thesedrugs are either administered systemically, or, more recently, they areintroduced directly into the periodontal pocket by site-specific drugdelivery methods utilizing a polymeric matrix material as a carrier.Such products include Atridox® and Actisite®. Another agent,chlorohexidine gluconate (an antiseptic) has been formulated into agelatin/glutaraldehyde matrix in the form of a small chip, thePeriochip®, which delivers a bactericidal dose of chlorohexidine to theperiodontal pocket. With these methods, drug concentrations in theperiodontal pocket are much higher than could be attained by systemicdosing. These systems provide a sustained release of the drug in theperiodontal pocket over a 7 to 10 day course of treatment. They are moredifficult to administer than an oral antibacterial agent, but bydelivering a high, sustained dose over the course of treatment, thesite-specific systems are less likely to cause bacterial resistancedevelopment, which is problematic with long-term systemic antimicrobialtreatment.

While these systems offer a possible alternative to periodontal surgeryfor treatment of refractory sites that have not responded to scaling androot planing procedures, the overall strategy of treatment ofperiodontal disease with antibacterial agents alone may be questioned.Although periodontal disease may be initiated by the presence of certainmicroorganisms, the present invention recognizes that it is aninflammatory condition that may be more effectively treated byattempting to decrease or eliminate the inflammatory response to thebacteria rather than the bacteria itself.

A variety of non-steroidal anti-inflammatory drugs (NSAIDs) have beenstudied as treatments for periodontal disease. These studies haveexamined NSAIDs delivered either topically, site-specifically orsystemically and some have been found to exhibit limited beneficialeffects. However, the NSAIDs only block the cyclooxygenase pathway inthe metabolism of arachidonic acid, thereby blocking formation of only aportion of the inflammatory mediators. When used systemically, NSAIDsalso may cause gastrointestinal side effects, which would be prohibitivefor long-term treatment. No NSAID is currently marketed specifically forthe treatment of periodontal disease.

Recently, Periostat® has been introduced for the treatment ofperiodontal disease. Periostat® is a low-dose formulation ofdoxycycline. Although doxycycline is known for its antimicrobialproperties, at the low dosages present in Periostat®, its effects aredue to inhibition of collagenase enzymes. Periostat® shows noantibacterial activity at the prescribed dosage. The clinical studiesshow results similar to those obtained with local delivery ofantibacterial agents.

The current methods for treatment of periodontal disease are costly,painful and often ineffective, discouraging many from seeking treatment.Of all the above-mentioned products, none provide a significant impacton the treatment of periodontal disease. A need therefore exists forsuch a product. The compositions and methods described herein addressesthis need.

SUMMARY OF THE INVENTION

Periodontal disease is highly prevalent and its progression can notalways be arrested by scaling, root planing and oral hygiene procedures.In these cases, alternatives or adjuncts to surgical treatment ofperiodontal disease are highly desired. Traditionally, thesealternatives have been limited to antibacterial agents. However,antibacterial treatment has proven to be unpredictable and oftenineffective. Although it is understood that bacteria are a necessarycomponent of the disease, the presence of suspected pathogenic bacteriadoes not automatically mean periodontal disease will develop. If thedisease does develop, there may be quiescent periods and exacerbationseven when the bacterial levels are relatively constant. The presentinvention proposes an approach that addresses the inflammatory aspect ofthe disease and suggests that the inflammatory response to the bacteriais the main factor both in the development and the progression of thedisease state and a more appropriate target of treatment than thebacteria.

The microorganisms that have been implicated in periodontal disease aregram-negative, anaerobic bacteria. These characteristics may be moreimportant than identifying the specific causative bacterial strain dueto the host effects they cause. All gram-negative bacteria haveendotoxin present in their cell wall. When the gram-negative, anaerobicbacteria present in the subgingival spaces die, endotoxins present inthe bacterial cell wall are released into the gingival sulcus. Thesetoxins cause minimal tissue damage on their own. More importantly, hostcells respond to the endotoxin by secreting a variety of inflammatorymediators (e.g., cytokines), which are capable of recruiting andmaintaining inflammatory cells at a tissue site. Cytokines act on hostcells causing overexpression and secretiorn of secretory phospholipaseA₂ (sPLA₂).

The enzyme sPLA₂ catalyzes hydrolysis of the sn-2 ester bonds ofmembrane phospholipids to liberate lysophospholipids and fatty acids,including arachidonic acid. Lysophospholipids have the ability to damagecells and membranes, but the arachidonic acid causes a cascade ofevents. Arachidonic acid is metabolized by two enzymatic pathways andsubsequently converted to proinflammatory substances includingleukotrienes (via lipoxygenase activity), thromboxanes andprostaglandins (both via cyclooxygenase activity). These chemicalmediators recruit cells of the immune system and the compliment cascadeto produce an exaggerated inflammatory response. In the periodontum,progressive tissue and eventually bone destruction may result if theseprocesses get out of control. The invention described herein proposesthat this is the core of the pathogenesis of periodontal disease, andthat attenuating or eliminating the inflammatory response is the key tothe treatment of the disease. The present invention thus providesinhibitors of SPLA₂ in order to prevent release of arachidonic acid frommembrane phospholipids, to stop the entire arachidonic acid cascade andthereby stop the destruction attributed to the inflammatory process.

Differences in the tendency of individuals to produce sPLA₂ whensubjected to bacterial endotoxin may explain the variability inperiodontal disease progression between individuals with similar localhost factors (e.g., plaque and calculus deposits). Variability in sPLA₂levels may also explain individuals who experience episodic active andinactive disease phases, with the disease being most active when sPLA₂is most actively produced. The present invention provides a potentinhibitor of SPLA₂ in order to halt progression of the disease.

Accordingly, other features of the invention include methods of treatingperiodontal disease in a mammal. The methods may include administeringan effective amount of an inhibitor of sPLA₂ to a mammal in need oftreatment. A wide variety of inhibitors of sPLA₂ may be advantageouslyused in the invention. In certain forms of the invention, the inhibitorsused in the method are selected from 1H-indole-3-acetamides,1H-indole-3-acetic acid hydrazides, 1H-indole-3-glyoxylamides, relatedstructures and mixtures thereof. In other embodiments of the invention,the inhibitors are selected from 1H-indole-1-acetamides,1H-indole-1-acetic acid hydrazides, 1H-indole-1-glyoxylamides, relatedstructures, and mixtures thereof. In further embodiments, the inhibitorsare selected from substituted pyrroles. Other inhibitors of sPLA₂ mayalso be advantageously used in the present invention, especially thosehaving similar sPLA₂ inhibitory activity as the inhibitors particularlydescribed herein.

The inhibitors of the invention are advantageously delivered in variouscarriers by a variety of routes. For example, the inhibitors may bedelivered systemically by an oral route, or directly to the periodontalpocket. The preferred carrier for direct delivery is a matrix such as afiber, chip or film made from a biocompatible polymeric material sizedfor introduction into the periodontal pocket. In one form of theinvention, the polymeric material is biodegradeable but may also benon-biodegradeable and removed after the treatment. The matrix may beformed into a device for treating periodontal disease in a mammal,wherein the matrix is impregnated with an effective amount of aninhibitor of sPLA₂. In yet other embodiments, the inhibitor may bedelivered topically to the oral cavity in a composition that includes acarrier such as a toothpaste, mouthwash, or chewing gum. The chewing gumtypically includes a gum base of a biocompatible polymeric material suchas an elastomer. Moreover, the inhibitor may be delivered to theperiodontal pocket by flushing the periodontal pocket with a compositionthat includes an oral irrigation solution carrier.

Other features of the invention include compositions for treatingperiodontal disease in a mammal. The inhibitors may be selected fromthose described above that are combined with a carrier as describedabove.

It is an object of the invention to provide compositions and effectivemethods for treating periodontal disease.

This and other objects and advantages of the present invention will beapparent from the descriptions herein.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to preferred embodiments andspecific language will be used to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended, such alterations and furthermodifications of the invention, and such further applications of theprinciples of the invention as illustrated herein, being contemplated aswould normally occur to one skilled in the art to which the inventionrelates.

The present invention relates generally to compositions that includesPLA₂ inhibitors and methods of using the compositions for the treatmentof periodontal disease. A wide variety of sPLA₂ inhibitors may beadvantageously used in the present invention. The inhibitors used in thepresent invention are small organic molecule pharmaceutical agents thatare hereby defined as having a molecular weight of no greater than about1000 g/mole. The molecular weight of the inhibitors is typically about300 to about 900 g/mole. Inhibitors of the 1H-indole-3-glyoxylamide,1H-indole-3-acetamide, and 1H-indole-3-acetic acid hydrazide structuraltypes, and related structures, as particularly described in U.S. Pat.Nos. 5,578,634; 5,654,326; 5,684,034; 5,733,923; 5,919,810; and5,919,943 may be utilized, as well as 1H-indole-1-acetamide,1H-indole-1-acetic acid hydrazide, and 1H-indole-1-glyoxylamidestructural types, and related structures, as particularly described inU.S. Pat. No. 5,641,800. Other examples of inhibitors that may beadvantageously used in the invention include substituted pyrroles asparticularly described in U.S. Pat. No. 5,919,774. These inhibitors, aswell as other small molecule pharmaceutical agents of similar inhibitorypotency, and pharmaceutically acceptable salts, solvates, or prodrugsthereof, are preferred for use in the invention.

In certain aspects of the invention, the inhibitors may be provided in acomposition that includes a carrier which allows the inhibitor to beplaced directly into the peridontal pocket. This carrier may be, forexample, a biocompatible polymeric material which may be retained in theperiodontal pocket for the duration of treatment or the carrier may be asolution which would be used to irrigate the periodontal pocket, thuswith limited retentive properties. For example, the substituted indoleor substituted pyrrole sPLA₂ inhibitors described above, or mixturesthereof, may be in a composition that includes a carrier. Other carriersinclude those that may be applied topically to the oral cavity,including a chewing gum carrier that includes a biocompatible polymericmaterial such as an elastomer, a toothpaste carrier, a mouthwash carrieror a solution used to irrigate the periodontal pocket. In other aspectsof the invention, the inhibitors and compositions of the presentinvention may be advantageously used in a method of treating periodontaldisease in a mammal, the method including administering to a mammal aneffective amount of the specified inhibitor of sPLA₂. In certain formsof the method, it is preferred to administer the inhibitors systemicallyby an oral route in carriers known to the art and described herein.

For the chemical structures described herein, certain defining terms areemployed as follows.

The term “alkyl ” means an aliphatic hydrocarbon which may be eitherstraight chain or branched and includes, for example, methyl, ethyl andstructural isomers of propyl, butyl, pentyl and hexyl.

The term “alkenyl ” as used herein refers to a straight or branchedhydrocarbon group having one double bond and includes, for example,vinyl, propenyl, crotonly, isopentyl, butenyl, and isomers thereof.

The term “alkynyl ” as used herein refers to a straight or branchedhydrocarbon group having one triple bond, and includes, for example,ethynyl, propynyl, 1-butynyl and isomers thereof.

The term “hydrocarbyl ” means an organic group containing only carbonand hydrogen.

The term “halo ” means fluoro, chloro, bromo or iodo.

The term “acidic group ” means an organic group which, when attached toan indole nucleus through suitable linking atoms (hereinafter defined asthe “acid linker”), acts as a proton donor capable of hydrogen bonding.Examples of such acidic groups include 5-tetrazolyl, SO₃H and thefollowing:

where n is 1 to 8, R₈₆ is independently selected from a hydrogen, ametal or C₁-C₁₀ alkyl and R₉₉ is hydrogen or C₁-C₁₀ alkyl.

The term “acid linker ” refers to a divalent linking group symbolized as“—(L_(a))—”, which has the function of joining the 4, 5, 6 and/or 7position of the indole nucleus to an acidic group, or other group asspecified herein, through the linking group [i.e., indolenuclei—(L_(a))—acidic group].

The term “acid linker length” refers to the number of atoms (excludinghydrogen) in the shortest chain of the linking group —(L_(a))—thatconnects the 4,5, 6 or 7 position of the indole nucleus with the acidicgroup. The presence of a carbocyclic ring in —(L_(a))—counts as thenumber of atoms approximately equivalent to the calculated diameter ofthe carbocyclic ring. Thus, a benzene or cyclohexane ring in the acidlinker counts as 2 atoms in calculating the length of —(L_(a))—.Examples of acid linker groups advantageously incorporated into theinhibitor include:

wherein

R₈₄ and R₈₅ are each independently selected from hydrogen, C₁-C₁₀ alkyl,hydroxy, or R₈₄ and R₈₅ taken together are =═;

is 1 to 8;

Z is a bond, O, N(C₁-C₁₀ alkyl), N(H), or S.

It can be seen that (a), (b) and (c) have acid linker lengths of 5, 7,2, and respectively, whereas the acid linker length of (d) will varydepending on p.

The term “amine ” includes primary, secondary and tertiary amines.

The term “metal ” includes metals known to the art, and especially thosethat may form salts such as alkali metals, including lithium sodium, andpotassium, and alkaline earth metals, such as calcium and magnesium.

The term “carbocyclic radicals ” is defined herein to mean radicalsderived from a saturated or unsaturated, substituted or unsubstituted 5to 14 membered organic nucleus whose ring forming atoms are solelycarbon atoms. Examples of carbocyclic radicals include cycloalkyl,cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl,tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl,phenyl-cyclohexenyl, acenaphthylenyl, anthracenyl, biphenyl, bibenzyzlyland bibenzylyl homologues represented by the following formula:

wherein n is from 1 to 8.

The term “heterocyclic radical ” refers to radicals derived frommonocyclic or polycyclic, saturated or unsaturated, substituted orunsubstituted heterocyclic nuclei having 5 to 14 rings atoms andcontaining from 1 to 3 heteroatoms selected from the group consisting ofnitrogen, oxygen or sulfur. Examples of such heterocyclic radicalsinclude pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl,phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl,thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl,benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl,indazolyl, imidazo(1,2-A)pyridinyl, benzotriazolyl, anthranilyl,1,2-benzisoxazolyl, benzoxazolyl, benzotriazolyl, purinyl, pyridinyl,dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl,phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl,quinazolinyl and quinoxalinyl. The heterocyclic radicals may besubstituted by non-interfering substituents.

The term “non-interfering substituents ” refers to radicals suitable forsubstitution at positions 4, 5 6 and/or 7 on the indole nucleus (i.e.,those positions that are substituted by R₄, R₅, R₆, and R_(7,)respectively), on the heterocyclic radicals and carbocyclic radicalsdefined herein or at other locations specified herein. Examples of suchnon-interfering substituents include C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₇-C₁₂ aralkyl, C₇-C₁₂ alkaryl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C₁-C₆ alkoxy, C₂-C₆alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₁₂alkoxyalkyl, C₂-C₁₂ alkoxyalkyloxy,C₂-C₁₂ alkylcarbonyl, C₂-C₁₂alkylcarbonylamino, C₂-C₁₂ alkoxyamino,C₂-C₁₂ alkoxyaminocarbonyl, C₂-C₁₂alkylamino, C₁-C₆ alkylthio, C₂-C₁₂alkylthiocarbonyl, C₀-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₆haloalkoxy, C₁-C₆ haloalkylsulfonyl, C₁-C₆haloalkyl, C₁-C₆ hydroxalkyl,C(O)O(C₁-C₆ alkyl), (CH₂)n—O—(C₁-C₆ alkyl), benzyloxy, phenoxy,phenylthio,—(CONHSO₂R₁₀), —CHO, amino, amidino, carbamyl, carboxyl,carbalkoxy, halo, (CH₂)_(n)—CO₂H, cyano, cyanoguanidinyl, guanidino,hydrazide,hydrazino, hydrazido, hydroxy, hydroxyamino, nitro, phosphono,SO₃H, thioacetal, thiocarbonyl and C₁-C₆ carbonyl, wherein n is from 1to 8 and R₁₀ is hydrogen, C₁-C₁₀ alkyl or a metal.

In a first aspect of the invention, compositions for treatingperiodontal disease in a mammal are provided that include an effectiveamount of an inhibitor of sPLA₂ in a carrier, such as a biocompatiblepolymeric material. In a first embodiment, the inhibitor has thefollowing structure:

or a pharmaceutically acceptable salt or prodrug derivative thereof,

wherein

R₁ is selected from the groups (a), (b), (c) or (d) wherein:

(a) is C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, C₄--C₂₀ alkynyl, carbocyclicradicals or heterocyclic radicals;

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents;

(c) is the group—(L)—(R₈₀) where —(L)— is a divalent linking group of 1to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfurwherein the combination of atoms in —(L)— are selected from the groupconsisting of (i) carbon and hydrogen only, (ii) sulfur only, (iii)oxygen only, (iv) nitrogen and hydrogen only, (v) carbon, hydrogen andsulfur only; and where R₈₀ is a group selected from (a) or (b);

(d) is a group having the formula:

wherein

each R₇₄ and R₇₅ are independently selected from hydrogen, hydroxy, orC₁-C₁₀ alkyl, or R₇₄ and R₇₅ taken together are =═; R₇₆ is aryl or arylsubstituted by halo, cyano, -CHO, hydroxy, nitro, phenyl, SH, C₁-C₁₀alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, amino, hydroxyamino, or a 5 to 8membered unsubstituted heterocyclic ring or substituted with anon-interfering substituent;

y is1 to 8;

R₂ is hydrogen, halo, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₁-C₂ alkylthio, C₁-C₃alkoxy, C2-C3 alkenyloxy, C2-C3 alkynyloxy, C3-C4 cycloalky, C3-C4cycloalkenyl, cyano, —CHO, amino, amidino, carbamyl, carboxyl,methylsulfinyl, hydrazino, hydrazido, C₁-C₂ hydroxyalkyl, thiocarbonylor C₁-C₂ carbonyl;

R₃ is

wherein

each R_(3a) is independently hydrogen, halo, or C₁-C₃ alkyl and X isoxygen or sulfur;

R₄, R₅, R₆, R7 are each independently hydrogen, phenoxy, halo, hydroxy,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, aryl,aralkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy, C₄-C₈cycloalkoxy, C₁-C₁₀ alkylthio, arylthio, thioacetal, —C(O)O(C₁-C₁₀alkyl), carboxyl, hydrazide, hydrazino, hydrazido, amino, nitro, SH,cyano, —NR₈₂ R₈₃ and —C(O)NR₈₂R₈₃, where R₈₂ and R₈₃ are independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ hydroxyalkyl, or taken together with N,form a 5 to 8-membered heterocyclic ring; or any two adjacenthydrocarbyl groups in the set R₄, R₅, R₆, R₇, combine with the ringcarbon atoms to which they are attached to form a 5 or 6 memberedunsubstituted carbocyclic ring, or substituted with a non-interferingsubstituent; or the group —(L_(a))—Q wherein —(L_(a))—is an acid linkerhaving an acid linker length of 1 to 10 and Q is —CON(R₈₂R₈₃), or anacidic group selected from 5-tetrazolyl, SO₃H, or the following:

wherein n is 1 to 8, R₈₂ and R₈₃ are as defined above, R₈₆ isindependently selected from a metal or C₁-C₁₀ alkyl and R₉₉ is hydrogenor C₁-C₁₀ alkyl. The 5 to 8 membered heterocyclic ring may be selectedfrom those heterocyclic radicals as described herein. Moreover, the 5 to6 membered carbocyclic rings include those 5 to 6 membered carbocyclicradicals described herein. The above compounds substituted at the 3position on the indole nucleus with groups 1, 2 or 3 as described aboveare hereinafter referred to as 3-substituted indoles.

It is further preferred that R₄ or R₅ is the group —(L_(a))—Q, whereinthe acid linker —(L_(a))— is a group having the formula:

wherein,

R₈₄ and R₈₅ are each independently selected from hydrogen, C₁-C₁₀ alkyl,hydroxy, or R₈₄ and R₈₅ taken together are =═;

p is 1 to 8; and

Z is a bond, O, N(C₁-C₁₀ alkyl), N(H), or S; and Q is an acidic group or—C(O)NR₈₂R₈₃ as defined in the first embodiment. Examples of divalentlinking groups —(L)— for R, include:

In a second embodiment of the invention, structure I may be substitutedas follows:

R₁ and R₂ are as defined in the first embodiment;

R₃ is group 1, wherein R_(3a) and X are as defined above for the firstembodiment;

R₄, R₅, R₆, R₇ are as described above in the first embodiment.

Another preferred group of 3-substituted indoles include those wherein:

R₁ and R₂ are as defined in the first embodiment;

R₃ is group 1, wherein R_(3a) and X are as defined above for the firstembodiment;

R₄ and R₅ are each independently selected from (i) and (ii) where;

(i) is hydrogen, halo, alkyl, or alkoxy; and

(ii) is the group —(L_(a))—Q, wherein —(L_(a))—is group D as describedabove, provided that at least one of R₄ or R₅ must be selected from (ii)and where R₈₄, R₈₅, p, Z, Q, R₈₂, R₈₃, n, R₈₆ and R₉₉ are as definedabove in the first embodiment; and

R₆ and R₇ are as defined for the first embodiment described above.

Other preferred 3-substituted indoles include those wherein structure 1is substituted as follows:

R₁ is a benzyl group that may be unsubstituted or substituted withnon-interfering substituents;

R₂ is methyl, ethyl, cyclopropyl, cyano or halo;

R₃ is group 1 as described above, wherein each R_(3a) is as described inthe first embodiment above and X is oxygen;

R₄ and R₅ are each independently selected from (i) and (ii) where;

(i) is hydrogen, halo, alkyl, or alkoxy; and

(ii) is the group —(L_(a))—Q, wherein —(L_(a))—is group D as describedabove, provided that at least one of R₄ or R₅ must be selected from (ii)and where R₈₄ and R₈₅ are independently, hydrogen or C₁-C₃ alkyl; p isfrom 1 to 4; Z is O; Q is an acidic group; and

R₆ and R₇ are non-interfering substituents.

Another preferred subclass of 3-substituted indoles include those where:

R₁ and R₂ are as defined in the first embodiment;

R₃ is group 2 as described above, wherein R_(3a) and X are as definedabove for the first embodiment.

R₄, R₅, R₆ and R₇ are as defined in the first embodiment.

In yet other embodiments, structure I may be substituted as follows:

R₁ and R₂ are as defined in the first embodiment;

R₃ is group 2 as described above, wherein R_(3a) and X are as defined 25for the first embodiment;

R₄ and R₅ are each independently selected from (i) and (ii) wherein:

(i) is hydrogen, halo, alkyl, or alkoxy; and

(ii) is group D as above, provided that at least one of R₄ or R₅ must beselected from (ii) and where R₈₄, R_(85,) p, Z, Q, R₈₂, R₈₃, n, R₈₆ and30 RgP are as defined above in the first embodiment; and

R₆ and R₇ are as defined in the first embodiment.

In further embodiments, structure 1 may be substituted as follows:

R₁ and R₂ are as defined in the first embodiment;

R₃ is group 3 as described above, wherein X is defined as above for thefirst embodiment.

R₄, R₅, R₆ and R₇ are as defined in the first embodiment.

In yet further embodiments, structure 1 is substituted as follows:

-R and R₂ are as defined in the first embodiment;

R₃ is group 3, wherein X is as defined above for the first embodiment;

R₄ and R₅ are each independently selected from (i) and (ii) where;

(i) is hydrogen, halo, alkyl, or alkoxy; and

(ii) is the group —(L_(a))—Q, wherein —(L_(a))—is group D as describedabove for the first embodiment, provided that at least one of R₄ or R₅must be selected from (ii) and where R₈₄, R₈₅, p, Z, Q, R₈₂, R₈₃, n, R₈₆and R₉₉ are as defined above in the first embodiment; and

R₆ and R₇ are as defined for the first embodiment described above.

In more preferred embodiments, a 3-substituted indole is providedwherein:

R₁ is a benzyl group that may be unsubstituted or substituted withnon-interfering substituents;

R₂ is methyl, ethyl, cyclopropyl. cyano or halo;

R₃ is group 3 as described above, wherein X is oxygen;

R₄ is —(L_(a))—Q, wherein —(L_(a))—is group D as described above; R₈₄and R₈₅ are hydrogen or C₁-C₃ alkyl; p is from 1 to 2, Z is 0; and Q isan acidic group as defined above; and

R₅, R₆ and R₇ are non-interfering substituents as described above.

The 3-substituted indoles described above, including the1H-indole-3-acetamides, 1H-indole-3-acetic acid hydrazides and the1H-indole-3-glyoxylamides may be synthesized by methods known to the artand as particularly described in U.S. Pat. Nos. 5,684,034; 5,578,634;5,654,326; 5,733,923; 5,919,810 and 5,919,943, all to Bach et al.

In yet other forms of the invention, the inhibitors are indolessubstituted at the 1 position on the indole nucleus with groups 1, 2 or3 described above (hereinafter referred to as 1-substituted indoles).These indoles have the following structure:

wherein

each R_(3a) is independently hydrogen, halo, or C₁-C₃ alkyl and X isoxygen or sulfur;

R₂ is hydrogen, halo, C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl,C₁-C₂ alkoxyl, C₁-C₂ alkylthio or is a non-interfering substituentselected from the group consisting of cyano, amino, amidino, halo,carbamyl, carboxyl, C₂-C₃ alkenyl, C₁-C₃ alkyl, cyclopropyl,cyclopropenyl, C₁-C₃ alkoxy, C₁-C₂ alkenyloxy, C₂-C₃ alkynyloxy, C,alkylsulfinyl, hydrazino, C₁-C₂ hydroxyalkyl, thiocarbonyl, and C₁-C₂carbonyl, or other non-interfering substituent that may include hydrogenthat has 1 to 3 atoms other than hydrogen;

R₃ is selected from groups (a), (b) and (c) wherein:

(a) is C₇-C₂₀ alkyl, C₇-C₂₀ alkenyl, C₇-C₂₀ alkynyl, carbocyclicradicals or heterocyclic radicals;

(b) is a member of (a) substituted with one or more non-interferingsubstituents, or

(c) is the group —(L)—R₈₀ wherein —(L)—is a divalent linking group of 1to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfurwherein the combination of atoms in —(L)—are selected from the groupconsisting of (i) carbon and hydrogen only, (ii) sulfur only, (iii)oxygen only, (iv) nitrogen and hydrogen only, (v) carbon, hydrogen andsulfur only; and where R₈₀ is a group selected from (a) or (b);

R₄ and R₅ are each independently selected from hydrogen, non-interferingsubstituent, carbocyclic radical, carbocyclic radical substituted withnon-interfering substituents, heterocyclic radical and heterocyclicradical substituted with non-interfering substituents;

R₆ and R₇ are independently selected from hydrogen, a non-interferingsubstituent, or the group —(L_(a))—(acidic group) wherein —(L_(a))—is anacid linker having an acid linker length of 1 to 10. In this embodiment,it is preferred that at least one of R₆ and R₇ is the group—(L_(a))—(acidic group). Unless otherwise indicated, the non-interferingsubstituents, carbocyclic radicals and heterocyclic radicals are asdescribed according to the definitions above.

For the 1-substituted indoles, it is preferred that, when R₃ is —(L)—,—(L)—is selected from those groups as described for —(L)—in the3-substituted indoles described above.

Furthermore, preferred R₈₀ substituents are selected from thecarbocyclic radicals as described above. Particularly preferredsubstituents for R₃ are selected from the following groups:

wherein R₁₀ is a radical independently selected from halo, C₁-C₁₀ alkyl,C₁-C₁₀ alkoxy, S-(C₁-C₁₀ alkyl) and C₁-C₁₀ haloalkyl, q is a number from0 to 4 and t is a number from 0 to 5.

Another preferred class of compounds is where R₇ is an acid linkerhaving a linker length 2 or 3, and the acid linker group, —(L_(a))—forR₇ is selected from the group represented by the following formula:

wherein:

Q is selected from the group CH₂, O, N(H), and S, and R₇₈ and R₇₉ areeach independently selected from hydrogen, C₁-C₁₀ alkyl, aryl, C₁-C₁₀alkaryl, C₁-C₁₀ alkaryl, carboxy, ethoxycarbonyl, and halo.

It is most preferred for R₇ that the acid linker —(L_(a))—is selectedfrom the following groups:

wherein

R₂₀ is O, S, N(R₂₁), CH₂; and R₂₁ is hydrogen or a C₁-C₄ alkyl.

Yet another preferred subclass of 1-substituted indoles are thosewherein R₆ has an acid linker substituent with an acid linker length of3 to 10 atoms, and the acid linker group, —(L_(a))—for R₆ is selectedfrom:

wherein r is a number from 1 to 7, s is 0 or 1, Q is selected from thegroup CH₂, O, N(H), and S; and R₅₁, and R₅₂ are each independentlyselected from hydrogen, C₁-C₁₀ alkyl, aryl, C₁-C₁₀ alkaryl, carboxy,ethoxycarbonyl, and halo. Most preferred are compounds where the acidlinker, —(L_(a))—for R₆ is selected from the following groups:

wherein

R₅₃ is hydrogen or C₁-C₄ alkyl, R₅₁ and R₅₂ are each independentlyselected from hydrogen, C₁-C₁₀ alkyl, aryl, C₁-C₁₀ alkaryl, C₁-C₁₀aralkyl, carboxy, ethoxycarbonyl and halo.

The 1-substituted indoles may be prepared by methods known to the art,and as particularly described in U.S. Pat. No. 5,641,800 to Bach et al.

In yet another aspect of the invention, compositions for treatingperiodontal disease are provided that include an effective amount of aninhibitor of sPLA₂, in a pharmaceutically acceptable carrier, such as acarrier that may be administered directly to the periodontal pocket,wherein the inhibitors are substituted pyrroles having the followingformula:

or a pharmaceutically acceptable salt thereof,

wherein

R₁ is hydrogen, C₁-C₄ alkyl, phenyl or phenyl substituted with one ortwo substituents selected from the group consisting of C₁-C₄ alkyl,C₁-C₄ alkoxy, phenyl(C₁-C₄)alkyl, C₁-C₄ alkylthio, halo and phenyl;

R₂ is hydrogen, C₁-C₄ alkyl, halo, C₁-C₄ alkoxy, or C₁-C₄ alkylthio;

R₃ and R₄ are each hydrogen, or when taken together are =═;

R₅ is amino or NHNH₂;

R₆ and R₇ are each hydrogen; or when one of R₆ and R₇ is hydrogen, theother is C₁-C₄ alkyl or (CH₂)_(n) —R₁₀ wherein R₁₀ is CO₂R_(11,)PO₃(R₁₁)₂, PO₄(R₁₁)₂ or SO₃R₁₁ wherein R₁₁ is independently hydrogen orC₁-C₄ alkyl and n is 1 to 4; or R₆ and R₇, taken together, are =═or =S;

X is (C₁-C₆)alkyl or (C₂-C₆)alkenyl which are substituted with R₈;or isphenyl substituted at the ortho position with R₈ or additionallyoptionally substituted with one or two substituents selected from thegroup consisting of hydrogen, C₁-C₄ alkyl, halo, C₁-C₄ alkoxy, or twosubstituents, when taken together with the phenyl group to which theyare attached, form a naphthyl group; wherein R₈ is —(CH₂),—R₁₀ and R₁₀,R₁₁ and n are as defined above; and

R₉ is hydrogen or C₁-C₄ alkyl.

Preferred substituted pyrroles are where:

R₁ is phenyl; R₂ is methyl or ethyl; R₅ is amino; R₆ and R₇ are eachhydrogen; X is (C₁-C₆)alkyl that may be substituted with R_(8;) or isphenyl substituted at the ortho position with R_(8,) wherein R₈ isCO₀₂R₁₁ and R₁₁ is as defined above; and R₉ is methyl or ethyl.

The substituted pyrroles may be prepared by methods known to the art,and as particularly described in U.S. Pat. No. 5,919,774 to Bach et al.

Included within the scope of the invention is the use ofpharmaceutically acceptable salts of the compounds included above.Pharmaceutically acceptable salts are known in the art and includealkali and alkaline earth salts such as lithium, sodium, potassium,calcium, magnesium and aluminum. Salts are typically prepared from thefree acid by treating the acid in solution with a base or by exposingthe acid to an ion exchange resin.

Further included within the invention is the use of inhibitors of theinvention that possess one or more chiral centers which may exist inoptically active forms. Moreover, when the inhibitors include an alkenylor alkenylene group, there exists the possibility of cis- andtrans-isomeric forms of the inhibitors. The use of R- and S-isomers andmixtures thereof, including racemic mixtures as well as mixtures ofcis-and trans-isomers, are also within the scope of this invention.Additional asymmetric carbon atoms may be present in a substituent groupsuch as an alkyl group. Use of all such isomers, as well as mixturesthereof, are contemplated. If a particular stereoisomer is desired, itcan be prepared by methods well know to the art, including use ofstereospecific reactions with starting materials which contain theasymmetric centers and are already resolved.

Further included within the invention is the use of prodrug derivativederivatives of the compounds described above. Prodrugs are derivativesof the compounds of the invention which have chemically or metabolicallycleavable groups and become, either by solvolysis or under physiologicalconditions, the compounds of the invention which are pharmaceuticallyactive in vivo. Prodrugs include acid derivatives known to the art, suchas esters prepared by reaction of the parent acidic compound with asuitable alcohol, or amides prepared by reaction of the parent compoundwith a suitable amine. Simple aliphatic or aromatic esters derived fromacidic groups pendent on the compounds of this invention are preferredprodrugs.

The compositions of the present invention include a pharmaceuticallyacceptable carrier, preferably for systemic oral delivery. Any suitablecarrier known in the art may be used. Carriers may be a solid, liquid ora mixture of a solid and a liquid. The carriers may take the form ofcapsules, tablets, pills, powders lozenges, suspensions, emulsions orsyrups. The carriers may include substances that act as a flavoringagents, lubricants, solubilizers, suspending agents, binders,stabilizers, tablet disintegrating agents and encapsulating materials.

Tablets for systemic oral administration may include excipients, asknown in the art, such as calcium carbonate, sodium carbonate, sugars(e.g., lactose, sucrose, mannitol, sorbitol), celluloses (e.g., methylcellulose, sodium carboxylmethyl cellulose), gums (e.g., arabic,tragacanth), together with disintegrating agents, such as maize, starchor alginic acid, binding agents, such as gelatin, collagen or acacia andlubricating agents, such as magnesium stearate, stearic acid or talc.

In powders, the carrier is a finely divided solid which is mixed with aneffective amount of a finely divided inhibitor.

In solutions, suspensions or syrups, an effective amount of theinhibitor is dissolved or suspended in a carrier such as sterile wateror an organic solvent, such as aqueous propylene glycol. Othercompositions can be made by dispersing the inhibitor in an aqueousstarch or sodium carboxylmethyl cellulose solution or a suitable oilknown to the art.

In preferred forms of the invention, compositions for direct delivery ofthe inhibitor to the periodontal pocket may include solid carriers, suchas polymers, fibers, chips and films. The solid carriers mayadvantageously be formed into a matrix that is configured, or sized, forintroduction into a periodontal pocket. The matrix, or other solidcarrier, which is impregnated with the inhibitor, is typically retainedin the periodontal pocket and allows release of the inhibitor. Suchmatrices, impregnated with an inhibitor of sPLA₂, may thusadvantageously form a device for treating periodontal disease. Thecarriers may alternatively be a liquid or a gel, and may be formulatedto allow retention of the drug in the periodontal pocket by, forexample, solidifying. Such compositions or devices for direct deliverymay be placed directly in the periodontal pocket and left in place overthe treatment period to achieve a therapeutic effect. The carriers maybe biodegradable and may be allowed to degrade, or may alternatively beremoved at the end of the treatment period.

In one embodiment, an effective amount of an inhibitor of sPLA₂ may becombined with, or dispersed in, a carrier formed from a biocompatiblepolymeric material. A wide variety of biocompatible materials fordelivery of therapeutic agents to the oral cavity are known in the art.For example, such polymers may be selected from cellulosic polymers,collagen, glycolic acid polymers, methacrylate polymers, ethylene vinylacetate copolymers, ethylene vinyl alcohol copolymers, polylactides andpolycaprolactone. The polymer may furthermore be an elastomer whosesolid form may be advantageously used in forming a chewing gum carrier.Moreover, when the polymeric material is in the form of a solid, such asa fiber, chip or film, the polymeric material is preferably impregnatedwith the inhibitor.

In one preferred form of the invention, a composition for direct oraldelivery includes an sPLA₂ inhibitor, or mixture of inhibitors,described above which is combined with a biodegradeable gel formulationbased on polylactides, such as poly(DL)lactide. A wide variety of suchformulations are known to the art and include, for example, a carrierincluding a poly(DL)lactide dissolved in a solvent, such asN-methyl-2-pyrrolidone. Such a carrier is available commercially underthe product name Atrigel®. The carrier may include, for example, about37% of a poly(DL)lactide dissolved in about 63% N-methyl-2-pyrrolidone.

In a preferred embodiment, typically when periodontal pockets are of asufficient depth (e.g., 5 mm or more), a composition for direct oraldelivery includes the inhibitors described above which are deliveredwith a solid carrier in the form of a chip that includes a biodegradablematrix of hydrolyzed gelatin that is cross-linked with glutaraldehydeand further includes glycerin and water. Such solid carrier chips areused to deliver an antibacterial agent in a product marketed under thename Periochipo. In the present case, the chip is typically impregnatedwith the inhibitor and is placed in the periodontal pocket.

In those embodiments wherein the polymer is an elastomer, the elastomermay serve as the gum base for a chewing gum carrier. Chewing gum, asknown in the art, contains an insoluble chewable gum base portion and awater-soluble bulk portion with various fillers and flavoring agents.The insoluble gum base may include the various elastomers, elastomersolvents, plasticizers, waxes, emulsifiers and inorganic fillers asknown in the art and as described, for example, in U.S. Pat. No.5,916,606 to Record et al. A wide variety of natural and syntheticelastomers known to the art may advantageously be used. The elastomersin the insoluble gum base portion may include, for example, styrenebutadiene copolymers, both natural and synthetic, and natural elastomerssuch as rubbers, guayule, and gums such as chicle, jelutong, balata, andlechi capsi. The water-soluble portion may include softeners, sweetenersand flavoring agents known to the art.

In yet other forms of the invention, compositions are provided thatinclude the inhibitor dispersed in other carriers, including atoothpaste carrier, solutions for oral irrigation of periodontal pocketsor a mouthwash carrier.

A wide variety of toothpaste formulations are known to the art, and asshown, for example, in U.S. Pat. No. 5,302,374 to Wagner. Theformulations typically include sodium fluoride, water, an abrasive suchas hydrated silica, and carriers such as glycerin, a sugar flavoringagent such as xylitol or sorbitol, sodium lauryl sulfate, cellulose gum,sodium saccharin or other flavoring agent, titanium dioxide and a base,such as sodium carbonate.

A wide variety of mouthwash formulations are also known to the art andas shown, for example, in U.S. Pat. Nos. 4,919,918 to Harrison et al.and 5,328,682 to Pullen et al. A mouthwash formulation may typicallyinclude coloring agents, flavoring agents, such as sorbitol, xylitol orsaccharin, alcohol or other antibacterial agents as known in the art.The mouthwash may also include sterile water, glycerin and polyethyleneglycol. Although the formulation may be alcohol-based, formulations thatare alcohol-free and based on, for example, acids and surface activeagents may advantageously be used. Such alcohol-free formulations arewell known in the art, and as described, for example, in U.S. Pat. No.4,919,918.

A wide variety of oral irrigation solutions known to the art may beused. For example, such solutions may include sterile water, glycerinand polyethylene glycol.

Other carriers known to the art may also be used, and include, forexample, ointments for topical delivery into which the inhibitor isdispersed.

In yet other forms of the invention, compositions are provided thatinclude the inhibitors described herein, along with one or moreantibacterial compounds known to the art. Examples of such antibacterialcompounds include chlorhexidine gluconate, iodine, sulfonamides,mercurials, phenolics, and antibiotics such as tetracycline, neomycin,kanamycin, doxycycline and metronidazole.

The compositions include amounts of the respective inhibitors effectivein treating periodontal disease. This therapeutic amount may vary,depending on the extent of periodontal disease, the route ofadministration, the potency of the inhibitor and whether otherinhibitors are administered. However, the compositions may typicallyinclude an amount of the inhibitor to provide a daily dose of about0.001 mg/kg to about 50 mg/kg of body weight of the inhibitor. Ofcourse, lower or higher dosages may be needed depending on the specificcase. As a tablet or capsule, typical unit dosage forms range from 0.01mg to about 1 g.

The inhibitors of the invention are effective in inhibiting SPLA₂ andare thus effective in inhibiting release of the fatty acid arachidonicacid. The inhibitors preferably inhibit sPLA₂ by at least about 30%,preferably at least about 50% and most preferably at least about 90%.Methods to determine the degree to which sPLA₂ is inhibited are wellknown to the art, and include, for example, assays which directlymeasure free sPLA₂ levels (i.e., sPLA₂ not bound to an inhibitor) or thelevels of other inflammatory mediators.

In yet another aspect of the invention, methods for treating periodontaldisease are provided. The methods include administering to a mammal inneed of treatment, such as a mammal with periodontal disease, aneffective amount of the inhibitors described above. The inhibitors maybe delivered with a carrier as described above.

The inhibitor may be delivered by several routes. For example, theinhibitor may be delivered systemically by oral administration,typically with carriers in the form of pills, tablets, lozenges,suspensions, emulsions or syrups as described above. The inhibitors mayalso be administered directly to the periodontal pocket. For example,the inhibitors may be delivered site-specifically to the periodontalpocket with the use of gel and the various polymer carriers describedabove. The polymer or other matrix carriers are advantageous in thatthey allow a high concentration and a controlled release of theinhibitor over a period of time.

A wide variety of mammals may be treated, including cats, dogs andpreferably humans.

Administration of the compositions directly into the periodontal pocket,such as by placing a matrix carrier impregnated with an inhibitor in theperiodontal pocket, is preferably performed after completion of scalingand root planing procedures, but may also be accomplished withoutperforming such procedures.

When administering the inhibitors in a liquid carrier, such as an oralirrigation solution, the solution may be used to flush the periodontalpocket. The solution may be administered directly to the periodontalpocket by syringe, as an irrigant solution for an ultrasonic scaler orby other appropriate methods of delivery known to the art.

The mammal is typically treated with an effective amount of theinhibitor. This amount will depend on the factors mentioned above.

Moreover, the duration of the treatment will also depend on the factorsmentioned above, as well as on the ability of the particular carrier tosustain release of the drug. For biodegradable carriers, the treatmentperiod will also be based on the retentive ability of the carrier.

The effectiveness of the various compositions administered forperiodontal disease in a mammal can be determined by measuring changesin various periodontal parameters known in the art after a period oftreatment with the compositions compared to treatment with scaling androot planing procedures alone, or no treatment at all. For example,probing depth measurements and radiographic analysis are standardanalyses for monitoring the progression of periodontal disease.

Periodontal probing measurements can record pocket depth (i.e., thedistance from the gingival margin to the depth of the gingival sulcus),or loss of attachment (i.e., the distance from the cementoenameljunction to the depth of the gingival sulcus).

Radiographic analyses use standardized radiographs to determine changesin bone height (based on linear measurements) and bone mass (based onradiographic density measurements).

Other measures of disease severity include gingival indices, whichassign scores to gingival sites based on the appearance or degree ofinflammation or the amount of bleeding upon probing. However, the othermethods described above are less subjective and thus more preferred.

As stated above, only selected examples of inhibitors that may beadvantageously used in the compositions and methods of the presentinvention are discussed herein. Other inhibitors of sPLA₂ known to theskilled artisan that are not specifically mentioned herein may also beused in the present invention, and preferably include inhibitors havingsimilar sPLA₂ inhibitory activity as the inhibitors described herein.Furthermore, the compositions described herein may also beadvantageously used to treat inflammation of tissue surrounding dentalimplants, known as peri-implantitis, using the same procedures describedherein.

Reference will now be made to specific examples illustrating thecompositions and methods described above. It is to be understood thatthe examples are provided to illustrate preferred embodiments and thatno limitation to the scope of the invention is intended thereby.

EXAMPLE 1 Inhibitor/Gel Carrier Composition

A bioresorbable flowable polymeric formulation can be made by dissolvingpoly(DL)lactide in N-methyl-2-pyrrolidone to form a solution of 63% byweight N-methyl-2-pyrrolidone and 37% by weight poly(DL)lactide. Aneffective amount of the inhibitor can be combined with the carrier.

The method of delivery can include placing the above formulation in onesyringe and including an effective amount of the sPLA₂ inhibitor (in asecond pharmaceutically inert carrier as described above) in a secondsyringe. After mixing, the viscous material may be applied to theperiodontal pocket where it will solidify upon contact with the gingivalcrevicular fluid. The drug can be released over a 7 to 10 day period ina concentration sufficient to achieve inhibition of sPLA₂ as the carrierbiodegrades.

EXAMPLE 2 Inhibitor/Ethylene Vinyl Acetate Copolymer Fiber CarrierComposition

Any of the substituted indoles, pyrroles or other sPLA₂ inhibitors maybe delivered with an ethylene vinyl acetate copolymer carrier. In orderto form an inhibitor/fiber carrier composition, effective amounts of theinhibitor may be combined with ethylene vinyl acetate copolymer and thecomposition can be extruded through the chamber of a Tinius OlsenExtrusion Plastometer. The chamber is typically heated to a temperaturebelow that at which the inhibitor decomposes. After the extrusion, theextruded material is then cooled to form fibers. The fibers can be about0.1 mm to about 1 mm in diameter.

EXAMPLE 3 Inhibitor/Toothpaste Composition

The toothpaste can include about 65% to about 90% by weight of a basecomponent that includes about 5-20% by weight water, about 10 to about40% by weight glycerin, about 20 to about 40% by weight of calciumcarbonate and about 20 to about 40% by weight silica. The toothpaste caninclude an effective amount of an sPLA₂ inihibitor.

While the invention has been illustrated and described in detail in theforegoing description, the same is to be considered as illustrative andnot restrictive in character, it being understood that only thepreferred embodiment has been shown and described and that all changesand modifications that come within the spirit of the invention aredesired to be protected. For example, although a method of treatingperiodontal disease utilizing the various inhibitors and compositions isdescribed herein, other oral inflammatory diseases may also be amenablefor such treatment, including peri-implantitis. Therefore, a method oftreating peri-implantitis, or other oral inflammatory diseases,utilizing the inhibitors and compositions described herein is alsoencompassed within this invention. In addition, all references citedherein are indicative of the level of skill in the art and are herebyincorporated by reference in their entirety.

What is claimed is:
 1. A method of treating periodontal disease in amammal, comprising: administering to said mammal in need of treatment aneffective amount of an inhibitor of secretory phospholipase A₂.
 2. Themethod of claim 1, wherein said inhibitor has the following structure:

or a pharmaceutically acceptable salt, or prodrug derivative thereofwherein R₁ is selected from the groups (a), (b), (c) or (d) wherein: (a)is C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, C₄-C₂₀ alkynyl, carbocyclic radicals orheterocyclic radicals; (b) is a member of (a) substituted with one ormore independently selected non-interfering substituents; (c) is thegroup —(L)—(R₈₀) where —(L)—is a divalent linking group of 1 to 12 atomsselected from carbon, hydrogen, oxygen, nitrogen, and sulfur wherein thecombination of atoms in —(L)—are selected from the group consisting of(i) carbon and hydrogen only, (ii) sulfur only, (iii) oxygen only, (iv)nitrogen and hydrogen only, (v) carbon, hydrogen and sulfur only; andwhere R₈₀ is a group selected from (a) or (b); (d) is a group having theformula:

wherein each R₇₄ and R₇₅ are independently selected from hydrogen,hydroxy, or C₁-C₁₀ alkyl, or R₇₄ and R₇₅ taken together are =═; R₇₆ isaryl or aryl substituted by halo, cyano, —CHO, hydroxy, nitro, phenyl,SH, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, amino, hydroxyamino,or a 5 to 8 membered unsubstituted heterocyclic ring or substituted withnon-interfering substituents; y is 1 to 8; R₂ is hydrogen, halo, C₁-C₃alkyl, C₂-C₃ alkenyl, Cl-C₂ alkylthio, C₁-C₃ alkoxy, C₂-C₃ alkenyloxy,C₂-C₃ alkynyloxy, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl, cyano, —CHO,amino, amidino, carbamyl, carboxyl, methylsulfinyl, hydrazino,hydrazido, C₁-C₂ hydroxyalkyl, thiocarbonyl or C₁-C₂ carbonyl; R₃ is

wherein each R_(3a) is independently hydrogen, halo, or C₁-C₃ alkyl andX is oxygen or sulfur; R₄, R_(5,) R₆, R₇ are each independentlyhydrogen, phenoxy, halo, hydroxy, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₈ cycloalkyl, aryl, aralkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀alkoxy, C₁-C₁₀ haloalkoxy, C₄-C₈ cycloalkoxy, C₁-C₁₀ alkylthio,arylthio, thioacetal, -C(O)O(C₁-C₁₀ alkyl), carboxyl, hydrazide,hydrazino, hydrazido, amino,nitro, SH, cyano, —NR₈₂R₈₃ and —C(O)NR₈₂R₈₃,where R₈₂ and R₈ ₃ are independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀hydroxyalkyl, or taken together with N, form a 5 to 8-memberedheterocyclic ring; or any two adjacent hydrocarbyl groups in the setR_(4,) R₅, R₆, R₇, combine with the ring carbon atoms to which they areattached to form a 5 or 6 membered unsubstituted carbocyclic ring, orsubstituted with a non-interfering substituent; or the group —(L_(a))—Qwherein —(L_(a))—is an acid linker having an acid linker length of 1 to10 and Q is an acidic group or -C(O)NR₈₂R₈₃, wherein R₈₂ and R₈₃ areindependently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ hydroxyalkyl, or takentogether with N, form a 5 to 8-membered heterocyclic ring.
 3. The methodof claim 2, wherein R₄ or R₅ are the group —(L_(a))—Q, wherein—(L_(a))—is an acid linker having the following formula;

wherein, R₈₄ and R₈₅ are each independently selected from hydrogen,C₁-C₁₀ alkyl, hydroxy, or R₈₄ and R₈₅ taken together are =═; p is 1 to8, Z is a bond, O, N(C₁-C₁₀ alkyl), N(H), or S.
 4. The method of claim1, wherein said inhibitor is administered systemically by an oral route.5. The method of claim 1, wherein said inhibitor is administereddirectly to the periodontal pocket in a carrier comprised of abiocompatible polymeric material.
 6. The method of claim 5, wherein saidinhibitor is administered in a chewing gum carrier comprised of saidpolymeric material, wherein said polymeric material is selected fromnatural and synthetic elastomers.
 7. The method of claim 1, wherein saidinhibitor is administered directly to the periodontal pocket in acarrier comprised of an oral irrigation solution.
 8. The method of claim1, wherein said inhibitor is administered topically to the oral cavityin a carrier selected from a toothpaste carrier or mouthwash carrier. 9.The method of claim 1, wherein said inhibitor is administered in acarrier that includes an antibacterial agent.
 10. The method of claim 1,wherein said inhibitor has the following structure:

or a pharmaceutically acceptable salt or prodrug derivative thereof,wherein R₁ is

wherein each R_(3a) is independently hydrogen, halo or C₁-C₃ alkyl and Xis oxygen or sulfur; R₂ is hydrogen, halo, C₁-C₃ alkyl, C₃-C₄cycloalkyl, C₃-C₄ cycloalkenyl, C₁-C₂ alkoxyl, C₁-C₂ alkylthio or anon-interfering substitutent selected from the group consisting ofcyano, amino, amidino, halo, carbamyl, carboxyl, C₂-C₃ alkenyl, C₁-C₃alkyl, cyclopropyl, cyclopropenyl, C₁-C₃ alkoxy, C₁-C₂ alkenyloxy, C₂-C₃alkynyloxy, C, alkylsulfinyl, hydrazino, C₁-C₂ hydroxyalkyl,thiocarbonyl, and C₁-C₂ carbonyl; R₃ is selected from groups (a), (b)and (c) wherein: (a) is C₇-C₂₀ alkyl, C₇-C₂₀ alkenyl, C₇-C₂₀ alkynyl,carbocyclic radicals or heterocyclic radicals; (b) is a member of (a)substituted with one or more independently selected non-interferingsubstituents; or (c) is the group —(L)—R₈₀ wherein —(L)—is a divalentlinking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen,nitrogen, and sulfur wherein the combination of atoms in —(L)—areselected from the group consisting of (i) carbon and hydrogen only, (ii)sulfur only, (iii) oxygen only, (iv) nitrogen and hydrogen only, (v)carbon, hydrogen and sulfur only; and where R₈₀ is a group selected from(a) or (b); R₄ and R₅ are each independently selected from hydrogen,non- interfering substituent, carbocyclic radical, carbocyclic radicalsubstituted with non-interfering substituents, heterocyclic radical andheterocyclic radical substituted with non-interfering substituents; R₆an-d R₇ are independently selected from hydrogen, a non-interferingsubstituent, or the group —(L_(a))—(acidic group) wherein —(L_(a))—is anacid linker having an acid linker length of 1 to
 10. 11. The method ofclaim 1, wherein said inhibitor has the following structure:

or a pharmaceutically acceptable salt thereof, wherein R₁ is hydrogen,C₁-C₄ alkyl, phenyl or phenyl substituted with one or two substituentsselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy,phenyl(C₁-C₄)alkyl, C₁-C₄ alkylthio, halo and phenyl; R₂ is hydrogen,C₁-C₄ alkyl, halo, C₁-C₄ alkoxy, or C₁-C₄ alkylthio; R₃ and R₄ are eachhydrogen, or when taken together are =═; R₅ is amino or NHNH₂; R₆ and R₇are each hydrogen; or when one of R₆ and R₇ is hydrogen, the other isC₁-C₄ alkyl or —(CH₂)_(n)R₁₀ wherein R₁₀ is —CO₂R₁₁, PO₃(R₁₁)₂,—PO₄(R₁₁)₂ or —SO₃R₁₁ wherein R₁₁ is independently hydrogen or C₁-C₄alkyl and n is 1 to 4; or R₆ and R_(7,) taken together, are =═or =S: Xis (C₁-C₆)alkyl or (C₂-C₆)alkenyl which are substituted with R₈; or isphenyl substituted at the ortho position with R₈ or additionallyoptionally substituted with one or two substituents selected from thegroup consisting of hydrogen, C₁-C₄ alkyl, halo, C₁-C₄ alkoxy, or twosubstituents, when taken together with the phenyl group to which theyare attached, form a naphthyl group; wherein R₈ is —(CH₂),—R₁₀ and R₁₀,R₁₁ and n are as defined above; and R₉ is hydrogen or C₁-C₄ alkyl.
 12. Acomposition for treating periodontal disease in a mammal, comprising: aneffective amount of an inhibitor of secretory phospholipase A₂ in acarrier comprised of a biocompatible polymeric material.
 13. Thecomposition of claim 12, wherein said polymeric material is selectedfrom the group consisting of glycolic acid polymers, methacrylatepolymers, ethylene vinyl acetate copolymers, ethylene vinyl alcoholcopolymers, polylactides and polycaprolactone.
 14. The composition ofclaim 13, wherein said polymeric materials further include collagen anda cellulosic polymer and are in the form a fiber configured for deliveryto the periodontal pocket.
 15. The composition of claim 12, wherein saidinhibitor is administered in a chewing gum carrier comprised of saidpolymeric material, wherein said polymeric material is selected fromnatural and synthetic elastomers.
 16. The composition of claim 12,wherein said carrier is further selected from a toothpaste carrier and amouthwash carrier.
 17. The composition of claim 16, wherein saidinhibitor has the following structure:

or a pharmaceutically acceptable salt, or prodrug derivative thereofwherein R₁ is selected from the groups (a), (b), (c) or (d) wherein: (a)is C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, C₄-C₂₀ alkynyl, carbocyclic radicals orheterocyclic radicals; (b) is a member of (a) substituted with one ormore independently selected non-interfering substituents; (c) is thegroup —(L)—(R₈₀) where —(L)—is a divalent linking group of 1 to 12 atomsselected from carbon, hydrogen, oxygen, nitrogen, and sulfur wherein thecombination of atoms in —(L)—are selected from the group consisting of(i) carbon and hydrogen only, (ii) sulfur only, (iii) oxygen only, (iv)nitrogen and hydrogen only, (v) carbon, hydrogen and sulfur only; andwhere R₈₀ is a group selected from (a) or (b), (d) is a group having theformula:

wherein each R₇₄ and R₇₅ are independently selected from hydrogen,hydroxy, or C₁-C₁₀ alkyl, or R₇₄ and R₇₅ taken together are =═; R₇₆ isaryl or aryl substituted by halo, cyano, —CHO, hydroxy, nitro, phenyl,SH, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, amino, hydroxyamino,or a 5 to 8 membered unsubstituted heterocyclic ring or substituted witha non- interfering substituent; y is 1 to 8; R₂ is hydrogen, halo, C₁-C₃alkyl, C₂-C₃ alkenyl, C₁-C₂ alkylthio, C₁-C₃ alkoxy, C₂-C₃, alkenyloxy,C₂-C₃ alkynyloxy, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl, cyano, —CHO,amino, amidino, carbamyl, carboxyl, methylsulfinyl, hydrazino,hydrazido, C₁-C₂ hydroxyalkyl, thiocarbonyl or C₁-C₂ carbonyl; R₃ is

wherein each R_(3a) is independently hydrogen, halo, or C₁-C₃ alkyl andX is oxygen or sulfur; R₄, R₅, R_(6,) R₇ are each independentlyhydrogen, phenoxy, halo, hydroxy, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₈ cycloalkyl, aryl, aralkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀alkoxy, C₁-C₁₀ haloalkoxy, C₄-C₈ cycloalkoxy, C₁-C₁₀ alkylthio,arylthio, thioacetal, —C(O)O(C₁-C₁₀ alkyl), carboxyl, hydrazide,hydrazino, hydrazido, amino,nitro, SH, cyano, NR₈₂R₈₃ and —C(O)NR₈₂R₈₃,where R₈₂ and R₈₃ are independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀hydroxyalkyl, or taken together with N, form a 5 to 8—memberedheterocyclic ring; or any two adjacent hydrocarbyl groups in the setR_(4,) R₅, R₆, R_(7,) combine with the ring carbon atoms to which theyare attached to form a 5 or 6 membered unsubstituted carbocyclic ring,or substituted with a non-interfering substituent; or the group—(L_(a))—Q wherein —(L_(a))—is an acid linker having an acid linkerlength of 1 to 10 and Q is and acidic group or —C(O)NR₈₂R₈₃, wherein R₈₂and R₈₃ are independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ hydroxyalkyl,or taken together with N, form a 5 to 8-membered heterocyclic ring. 18.The composition of claim 17, wherein R₄ or R₅ are the group —(L_(a))—Q,wherein —(L_(a))—is an acid linker having the following structure:

wherein, R₈₄ and R₈₅ are each independently selected from hydrogen,C₁-C₁₀ alkyl, hydroxy, or R₈₄ and R₈₅ taken together are =═; p is 1 to8, and Z is a bond, O, N(C₁-C₁₀ alkyl), N(H), or S.
 19. The compositionof claim 17, wherein said composition further includes an antibacterialagent.
 20. The composition of claim 16, wherein said inhibitor has thefollowing structure:

or a pharmaceutically acceptable salt or prodrug derivative thereof,wherein R₁ is

wherein each R_(3a) is independently hydrogen, halo or C₁-C₃ alkyl and Xis oxygen or sulfur; R₂ is hydrogen, halo, C₁-C₃ alkyl, C₃-C₄cycloalkyl, C₃-C₄ cycloalkenyl, C₁-C₂ alkoxyl, C₁-C₂ alkylthio or anon-interfering substitutent selected from the group consisting ofcyano, amino, amidino, halo, carbamyl, carboxyl, C₂-C₃ alkenyl, C₁-C₃alkyl, cyclopropyl, cyclopropenyl, C₁-C₃ alkoxy, C₁-C₂ alkenyloxy, C₂-C₃alkynyloxy, C, alkylsulfinyl, hydrazino, C₁-C₂ hydroxyalkyl,thiocarbonyl, and C₁-C₂ carbonyl; R₃ is selected from groups (a), (b)and (c) wherein: (a) is C₇-C₂₀ alkyl, C₇-C₂₀ alkenyl, C₇-C₂₀ alkynyl,carbocyclic radicals or heterocyclic radicals; (b) is a member of (a)substituted with one or more independently selected non-interferingsubstituents; or (c) is the group —(L)—R₈₀ wherein —(L)—is a divalentlinking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen,nitrogen, and sulfur wherein the combination of atoms in —(L)—areselected from the group consisting of (i) carbon and hydrogen only, (ii)sulfur only, (iii) oxygen only, (iv) nitrogen and hydrogen only, (v)carbon, hydrogen and sulfur only and where R₈₀ is a group selected from(a) or (b); R₄ and R₅ are each independently selected from hydrogen,non-interfering substituent, carbocyclic radical, carbocyclic radicalsubstituted with non-interfering substituents, heterocyclic radical andheterocyclic radical substituted with non-interfering substituents; R₆and R₇ are independently selected from hydrogen, a non-interferingsubstituent, or the group —(L_(a))—(acidic group) wherein —(L_(a))—is anacid linker having an acid linker length of 1 to 10, provided that atleast one of R₆ and R₇ must be the group —(L_(a))—(acidic group). 21.The composition of claim 20, wherein said composition further includesan antibacterial agent.
 22. The composition of claim 16, wherein saidinhibitor has the following structure:

or a pharmaceutically acceptable salt thereof, wherein R₁ is hydrogen,—(C₁-C₄) alkyl, phenyl or phenyl substituted with one or twosubstituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, phenyl(C₁-C₄)alkyl, C₁-C₄ alkylthio, halo and phenyl; R₂ ishydrogen, C₁-C₄ alkyl, halo, C₁-C₄ alkoxy, or C₁-C₄ alkylthio; R₃ and R₄are each hydrogen, or when taken together are =═; R₅ is amino or-NHNH₂;R₆ and R₇ are each hydrogen; or when one of R₆ and R₇ is hydrogen, theother is C₁-C₄ alkyl or (CH₂)_(n)—R₁₀ wherein R₁₀ is CO₂R₁₁, PO₃(R₁₁)₂,PO₄(R₁₁)₂ or SO₃R₁₁ wherein R₁₁ is independently hydrogen C₁-C₄ alkyland n is 1 to 4; or R₆ and R₇, taken together, are =O or =S; X is(C₁-C₆)alkyl or (C₂-C₆)alkenyl which are substituted with R₈; or isphenyl substituted at the ortho position with R₈ or additionallyoptionally substituted with one or two substituents selected from thegroup consisting of hydrogen, C₁-C₄ alkyl, halo, C₁-C₄ alkoxy, or twosubstituents, when taken together with the phenyl group to which theyare attached, form a naphthyl group; wherein R₈ is —(CH₂)_(n)—R₁₀ andR₁₀, R₁, and n are as defined above; and R₉ is hydrogen or C₁-C₄ alkyl.23. The composition of claim 22, wherein said composition furtherincludes an antibacterial agent.
 24. A device for treating periodontaldisease in a mammal, comprising: a matrix sized for introduction into aperiodontal pocket for treatment of periodontal disease, said matriximpregnated with an effective amount of an inhibitor of secretoryphospholipase A₂.